VOL. XXXIII.

FF3 4

No. 1

CELL EPITHELIOMA.*

WITH THE REPORT OF 59 CASES. BERNARD F. SCHREINER, M.D., F.A.C.S. BURTON T. SIMPSON, M.D.,

THEODOR MÜELLER, M.D.,

BUFFALO, N. Y.

From the standpoint of the general practitioner, three types of epithelioma most frequently are encountered. These are of the greatest importance from the viewpoint of diagnosis, prognosis, and treatment. We may for the sake of convenience divide epithelioma into three large groups:

1. Basal cell epithelioma, with which we are chiefly concerned in this paper.

2. The prickle cell epithelioma or so-called spinocell epithelioma which forms pearls.

3. The mucous membrane epithelioma which springs from mucous membrane surfaces. The second and third groups, namely the prickle cell epithelioma and the mucous membrane epithelioma will be reported on at some future time.

In the first group, basal cell epithelioma or carcinoma, as it is sometimes called, about 90% of the cases appear on the face, chiefly affecting the nose, cheeks, forehead, and eyelids, all notably above a line drawn on a level with the upper lip. They sometimes occur on the hands, arms, legs, shoulders, and abdomen, of which we had one very remarkable

case.

Basal cell epithelioma is rare before the age of thirty years and most common between the ages of forty to fifty according to various authors. The ages of our cases were as follows: in the fourth decade there were two cases; in the fifth, nine cases; in the sixth, seventeen; in the seventh, there were twenty; in the eighth, there were eight; and in the ninth there were three. The ratio that usually is given between male and female is three to one. Of our cases there were thirty-seven males and twenty-two females.

The lesions may occur singly but multiplicity of the lesions is noteworthy in this type of growth.

The duration of the lesions in our cases before

From the State Institute for the Study of Malignant Disease. Read at the Buffalo Academy of Medicine, October 2. 1918.

oma.

Fig. 1.

designated by various names, as sarcoma, adenoid epithelioma, and especially by Braun, as endotheliKrompecher made a very careful study of the literature but acknowledged that he was much confused concerning what was really meant by the tumors described by different authors.

Krompecher believed that this type of tumor took its origin either from the columnar basal layer of the epidermis or from the basal cells of the hair follicles or skin glands. The following year Borrman made extensive studies of this type of tumor, agreeing with Krompecher that they were not endothelioma, but true epithelial tumors, but disagreed concerning their origin, believing that they sprang from embryonal nests of the skin epithelium and only became connected with the skin epithelium as shown in Krompecher's illustrations, secondarily. Borrman gave to these tumors the name of "corium carcinoma." Mallory believes that these tumors. always spring from the hair matrix cells and has

named them "hair matrix carcinoma," It is probable that the site of origin is from the basal cells, either of the epidermis, hair follicles or skin glands and probably quite frequently from the pre-existing benign tumors of the skin glands, and also of nevi, for many of these tumors are accompanied by a preceding history of a nodule existing for a number of years, most always with an increasing rapidity of growth during the few preceding months. One of our lesions showed a distinct transformation from a sebaceous adenoma; and in one other instance these tumors, which were multiple, occurred in the axilla and groin following a chronic seborrhea which had existed for a number of years. Grossly, these tumors may vary in size from the head of a pin to the size of an orange and while they

The tumor cell in all types is about the same, being composed of small cells, round, cuboidal or spindle, with scanty protoplasm, and with a deeply staining, solid nucleus. Mitotic figures are very common. The cells arrange themselves on the periphery of the process in such a manner as to resemble very closely the columnar cells in the hair sheaths and also the basal cells in the epidermis. It is probably this resemblance which caused Krompecher to designate them as "basal cell carcinoma." The intercellular connective tissue varies considerably as in all epithelial neoplasms and is probably a biological phenomena, showing the relative rapidity of cell growth between tumor cells and stroma cells. In some cases the intercellular connective tissue predominates and one might refer to these

are usually nodular, they may also be irregular in shape. Very frequently they are elevated and may even be papillar. They are situated superficially in the skin and have a great tendency to ulcerate. On the cut surface they may be solid or may have a cystic appearance.

Histologically they all may be divided into two general groups: the one, solid and the other, alveolar. The solid variety which comprises 75% of these tumors, is made up of solid masses of cells which have a tendency to form processes which penetrate into the connective tissue of the corium forming a picture which has been likened to point lace. The cells may be round or spindle shaped, depending probably upon pressure and resistance conditions. The alveolar form, which comprises 25%, usually occur with an adenomateous appearance or in some cases may be tubular, in which case the tubules sometimes resemble very strikingly the ducts of the suderiferous glands. Occasionally the alveoli become enlarged, causing a cystic appearance. In about 15% of the cases there were tumors which showed mixture of these types.

Fig. 4-Before Treatment.

Fig. 5-After Treatment.

tumors as scirrhus. Metastases have not been observed in this series of cases.

These lesions run a more or less slow course according to the rapidity of the neoplastic growth, the nutrition of the part, and the resistance of the invaded tissue. As long as the epidermis remains intact, that is, as long as there is no ulceration, (in our cases this would include those that were reported as pimples, warts, and moles), the growth is extremely slow. After ulceration has occurred the cells multiply very rapidly. If they are unable to invade the surrounding tissue a fungus-like growth is the result. The lesion may heal in part spontaneously, but never entirely.

The classifications which have been made by different authors based on the clinical aspects represent only different stages in the development of some of the neoplasms, certain factors being common to all of them, only the clinical expression of the disease varying when we speak of rodent ulcer, or rolled edge ulcer, etc. According to the clinical course, some authors divide basal cell epithelioma into seven groups:

1. Flat rodent ulcer.

2. Nodular epithelioma.

3. Rolled edge epithelioma.

4. The depressed scar-like cancer.

5. Morphea-like.

6. Fungating epithelioma.

7. Deep ulcerating.

JOURNAL OF SURGERY.

which resulted in death. Thirdly, an attempt at healing may take place with the formation of a depressed scar, as in the fourth group, described by Hazen. The edge of the ulcer is slightly elevated and always indurated, the induration being due to the inflammation which usually exists, as well as the multiplication of cells. The diagnosis in the

I. The flat rodent ulcer is the most common. It begins usually as a reddish or pearl gray, smooth nodule with superficial ulceration taking place early. The ulcerated area is covered by an adherent black or dark brown crust which, from time to time, drops off or is picked off by the patient. When this occurs there is slight bleeding and the ulcera

hyperkeratosis, or more rarely some of the simple inflammations. After the ulceration appears, syphilis and lupus vulgaris must be considered.

II. The second group of Hazen's, the nodular type, usually arises from a preëxisting lesion which the patient may describe as a pimple, a wart, or a mole. A pearly nodule first forms and grows slowly, which in the course of a year or two may attain

ted area becomes larger. The growth is always slow and may take from one to ten years to attain the diameter of one to two centimeters. Induration is always present. On inspection with a hand lens small pearly nodules can be seen just at the edge of the ulceration. The skin around the edge looks shiny and is under tension. The tissue beneath the scab looks like ordinary granulation tissue. If this lesion is undisturbed or ineffectually treated one of several things may happen; first, there may be widespread superficial ulceration with or without the formation of fungating tumor masses (like group 6); second, there may be invasion and destruction of the neighboring tissues resulting in large ulcerating cavities which may become secondarily infected with the ordinary pus-forming organisms or putrefactive bacteria. In one of our cases the orbital cavity was involved with complete destruction of the orbit. In two cases the aural cavity was invaded, in one case, the auditory meatus. and, in the other, invasion of the temporal bone and mastoid cells with the destruction of the tables of the skull; and later an infection of the meninges

Fig. 7-After Treatment.

the size of one centimeter and be elevated above the surrounding skin. It is hard and firm to the touch, of a white or greyish appearance, with small dilated vessels running into the tumor. Later ulceration occurs and assumes the type of a rodent ulcer.

III. The rolled edge ulcer. . We have observed one case on the abdomen. They grow much more rapidly and may be slow to ulcerate. These growths have a distinct semi-globular edge with a depression in the center, the edge is extremely hard and the skin over it is tense, thick, and shiny. There are numerous dilated vessels extending into the normal skin. The late course of this type of basal cell epithelioma is the same as that of the two preceding types.

IV. The depressed scar-like epitheliomas usually start as a small subepidermal nodule, the skin over it remaining intact. They commonly are seen on the cheeks and temples. The nodule flattens out and slowly spreads below an edge of rete and as a result the appearance is identical with that of a depressed scar.

V. The morphea-like epithelioma has been described in detail by Heidingsfeld, Journal Cutaneous

Diseases, 1913, XXXI, 379. These lesions start as small nodules situated on the temples or malar eminences and are sharply defined and spread very slowly, taking four or five years to reach the diameter of one to two centimeters. They are sharply defined lesions with slightly elevated pearly border, the center white or yellow-white and depressed. The edges are very hard to the touch and the center feels leathery. There may be smaller ulcerated areas along the edges or in the center of the growth. We have not observed this type.

VI. The fungating basal cell epithelioma is usually caused by the cells proliferating more rapidly than they can invade, so that the growth must necessarily be outward. The surface may be smooth and resemble anemic granulation tissue, although they

cell epithelioma in which there is no metastasis. As the basal cell epithelioma of the skin is a superficial tumor, it, therefore, does not seem difficult to destroy all cancerous tissue and thus obtain a permanent cure. Even rather advanced cases are amenable to treatment. The infrequency of metastases increases the chances for a permanent cure, yet in spite of this there are among our cases many who had previously received medical attention without success. X-ray, caustics, and the thermocautery had been used or the tumor had been removed surgically. The effect was either a speedy recurrence after temporary healing, or a more rapid extension of the lesion.

For the treatment in our cases we used the following procedures, either alone or combined: ful

bleed at the slightest provocation. This type of tumor must be differentiated from the rapid-growing fungating type of pearl forming epithelioma as well as from some of the granulomata, granuloma pyogenicum, blastomycocis, and simple exuberant granulation tissue.

VII. The deep ulcer type is usually the result of injudicious treatment. The base of the ulcer is usually very irregular, with much discharge of pus of a foul odor, and the patient is toxic from absorption. Death usually takes places from hemorrhage or infection.

In the diagnosis of basal cell epithelioma, the following points are important: first, its location; second, the spontaneous origin of the lesion, from a pimple, wart, mole, or scaling skin (hyperkeratosis); third, the slow growth; fourth, the induration which exists no matter how small the lesion is; fifth, the progressive nature of the lesion, attempts at healing but never healing entirely; sixth, metastases are rarely if ever observed; seventh, biopsy, this being the only positive way of distinguishing between basal cell epithelioma and early prickle

Fig. 10.

guration, excision, radium and x-ray treatment. Fulguration has only a local effect which is practically the same as cauterization or coagulation of the tissue. It does not possess any advantage over the thermocautery in the treatment of basal cell epithelioma. We treated only two cases with fulguration. One of them healed promptly within 23 days, the other was fulgurated several times but remained stationary and healing at last was obtained by radiation.

Six basal cell epitheliomas were excised. All patients so treated were healed and remained well, some of them for more than three years. This success may be explained by the fact that we operated only on carefully selected cases. Not all cases, owing to their size and location, causes dealt with surgically.

In 19 cases we applied radium. We used it in the form of radium bromide, of which 51 mgs. were applied in metal applicator. In 9 cases the treatment was successful and a clinical cure has been obtained. One of these cases, however, sustained a severe radium burn which healed only after eight

months. In another case of this group it is doubtful whether the success can be ascribed to the effect of the radium alone. This patient with an ulcerated lesion on his nose had been fulgurated twice without success. Then he received within sixteen days two mild erythema doses of unfiltered x-rays, whereupon his lesion showed considerable improvement. Eight days after the last x-ray treatment, before the full effect of the x-rays had time to develop, the ulcer was radiated for three hours with radium. It is, therefore, not improbable that this lesion might have healed without the radium application. The favorable influence of the radium rays in the successful treatments could usually be noticed after two weeks, while it took from 1-2 months from the beginning of the treatment until the le

They can be divided into two groups. The first group contains thirteen cases which were treated with fractional filtered and unfiltered x-ray doses of varying penetration. Most of these cases showed a slight erythema; four of these thirteen cases remained refractory after temporary improvement. The other nine cases were pronounced clinically well within 3-10 weeks and are well at this time.

The second group contains forty-one cases, eleven of which are still under treatment. With these the was to destroy, if possible, with a single erythema dose all carcinomatous tissue. All were ulcerated, and in all the ulcerated lesion healed. In only one instance the scar remained slightly elevated. It is to be regretted that this patient did not report for further observation and treatment. All other cases

sion had disappeared. One patient is still under treatment, almost well. In the nine remaining cases the radium treatment did not prove satisfactory. Some of these showed at first some improvement, but then remained stationary; in one case the ulcer even progressed. Three of these cases which were refractory to radium were later on treated with x-rays and were healed promptly. On the other hand, among these nine cases were four which had not responded to many applications of x-rays and which also could not be influenced by radium. Our success with radium in basal cell epithelioma (50%) is, therefore, not very encouraging. Perhaps the amount of radium at our disposal is not sufficient for all cases, though it was large enough to produce a burn; perhaps we have not yet found the proper technic as to the filtration and doses of the radium. It is also possible that the failure of the radium treatment in some cases is due to the quality of the radium rays; their wave-length is probably too short and their penetration too high to be sufficiently absorbed by the tissue.

Fifty-four cases have been treated with x-rays.

Fig. 12-Before Treatment.

Fig. 13-After Treatment.

(97%) healed with scars that were quite satisfactory from a cosmetic point of view. The deliberately produced erythema of the skin did not inconvenience the patient in any way and disappeared after 2-3 weeks. The first improvement was usually noticed 1-2 weeks after the application of x-rays. The time required for healing varied between 3 and 6 weeks and depended upon the size of the new-growth. The time necessary for healing was prolonged somewhat in two patients who suffered from very extensive tumors which had already invaded the deeper layers of the subcutis.

The difference between these two groups is too great to be overlooked and speaks decidedly in favor of the so-called "massive dose treatment," which consists of few rather powerful applications, as recommended by MacKee and Remer and by.../ Pusey. The treatment with frequent small doses, the so-called "fractional dose" method, originated from the idea that it would not damage the healthy skin and tissue overlying the tumor. Of course it is absolutely necessary to pay strict attention to the skin when giving the so-called "deep x-ray treat